The complement system comprises more than 30 soluble and cell-bound proteins and plays an important role in both innate and acquired immunity, particularly in the body's response to infection. In the absence of a triggering event, many complement proteins exist primarily in an inactive, proenzyme form. Following activation, often by proteolytic cleavage, they participate in an enzymatic cascade leading to a number of downstream events such as lysis of cells, bacteria and viruses, opsonization, and activation of immune responses such as inflammation and cytokine secretion.
Complement activation occurs via three main pathways, known as the classical, alternative, and lectin pathways (Kuby Immunology, 2000). The classical pathway is usually triggered by binding of a complex of antigen and IgM or IgG antibody to C1 (though certain other activators can also initiate the pathway). Activated C1 cleaves C4 and C2 to produce C4a and C4b, in addition to C2a and C2b. C4b and C2a combine to form C3 convertase, which cleaves C3 to form C3a and C3b. Binding of C3b to C3 convertase produces C5 convertase, which cleaves C5 into C5a and C5b. C3a, C4a, and C5a are anaphylotoxins and mediate multiple reactions in the acute inflammatory response. C3a and C5a are also chemotactic factors that attract immune system cells such as neutrophils.
The alternative pathway is initiated by microbial surfaces and various complex polysaccharides. In this pathway, C3b, resulting from cleavage of C3, which occurs spontaneously at a low level, binds to targets, e.g., on cell surfaces and forms a complex with factor B, which is later cleaved by factor D, resulting in a C3 convertase. Cleavage of C3 and binding of another molecule of C3b to the C3 convertase gives rise to a C5 convertase.
The C5 convertases produced in both pathways cleave C5 to produce C5a and C5b. C5b then binds to C6, C7, and C8 to form C5b-8, which catalyzes polymerization of C9 to form the C5b-9 membrane attack complex (MAC). The MAC inserts itself into target cell membranes and causes cell lysis. Small amounts of MAC on the membrane of cells may have a variety of consequences other than cell death.
A third complement pathway, the lectin complement pathway is initiated by binding of mannose-binding lectin (MBL) and MBL-associated serine protease (MASP) to carbohydrates. In the human lectin pathway, MASP-1 and MASP-2 are involved in the proteolysis of C4, C2 and C3, leading to a C3 convertase described above.
Complement activity is regulated by members of the endogenous “regulators of complement activation” (RCA) family, also called “complement control proteins” (CCPs), which include complement receptor type 1 (CR1; C3b:C4b receptor), complement receptor type 2 (CR2), membrane cofactor protein (MCP; CD46), decay-accelerating factor (DAF), complement factor H (fH), complement receptor-related protein y (CRRY), and C4b-binding protein (C4bp). CCPs are characterized by multiple (typically 4-56) homologous motifs known as short consensus repeats (SCR), complement control protein (CCP) modules, or SUSHI domains (Reid, K B M and Day, A J, Immunol Today, 10:177-80, 1989). Complement control proteins negatively regulate the complement system, e.g., by accelerating the normal decay of convertases and/or functioning as cofactors for factor Ito enzymatically cleave C3b and/or C4b into smaller fragments.
While complement activation plays important roles in the innate and adaptive immune systems, the complement system is increasingly recognized to be involved in tissue injury during a variety of ischemic, inflammatory, and autoimmune diseases (Makrides, S C, Pharm Rev., 50(1): 59-87, 1998; Lisczewski, M K and Atkinson, J P, in The Human Complement System in Health and Disease, Volanakis, J E and Frank, M M, eds., Dekker, New York, pp. 149-66, 1998). Complement inhibition has been proposed as a therapeutic strategy for many such diseases. Unfortunately, a number of complement inhibitors have been less successful in the clinic than had been hoped. Nonetheless, complement inhibition remains an attractive option. Thus there is a need in the art for new compositions and methods for productively harnessing complement inhibition as a therapeutic modality for a variety of complement-mediated disorders.